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The clinical appearances of children with diastrophic dysplasia showing the characteristic craniofacial features (A–C).
Source publication
Objective
Accurate understanding of the cause of the underlying pathology in children with diastrophic dysplasia would help in designing targeted management of their locomotion.Methods
Diastrophic dysplasia was diagnosed in twelve patients (nine girls and three boys; age range 1–14 years), all of whom presented with small stature and apparent short...
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... limitation of motion of peripheral joints, progressive postnatal dorsal lordosis and scoliosis were present. All patients manifested congenital contractures of the elbows, wrists, hips and knees associated with severe foot deformities (bilateral talipes equinovarus). Children with diastrophic dysplasia have characteristic craniofacial features (Fig. 1). Figure 1A shows a 10-year-old boy with severe short stature, thickened ear lobes and multiple contractures (elbows, pelvis, and knees). Figure 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. Figure 1C shows a 6-monthold boy with ...
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... with diastrophic dysplasia have characteristic craniofacial features (Fig. 1). Figure 1A shows a 10-year-old boy with severe short stature, thickened ear lobes and multiple contractures (elbows, pelvis, and knees). Figure 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. ...
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... with diastrophic dysplasia have characteristic craniofacial features (Fig. 1). Figure 1A shows a 10-year-old boy with severe short stature, thickened ear lobes and multiple contractures (elbows, pelvis, and knees). Figure 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. Figure 1C shows a 6-monthold boy with micromelic dwarfism, a characteristic craniofacial contour and contractures of the elbows and knees. ...
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... 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. Figure 1C shows a 6-monthold boy with micromelic dwarfism, a characteristic craniofacial contour and contractures of the elbows and knees. Figure 1D shows a 12-year-old girl whose knees had been operated on to relieve the contractures; however, the contractures had recurred. ...
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... 1C shows a 6-monthold boy with micromelic dwarfism, a characteristic craniofacial contour and contractures of the elbows and knees. Figure 1D shows a 12-year-old girl whose knees had been operated on to relieve the contractures; however, the contractures had recurred. ...
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... limitation of motion of peripheral joints, progressive postnatal dorsal lordosis and scoliosis were present. All patients manifested congenital contractures of the elbows, wrists, hips and knees associated with severe foot deformities (bilateral talipes equinovarus). Children with diastrophic dysplasia have characteristic craniofacial features (Fig. 1). Figure 1A shows a 10-year-old boy with severe short stature, thickened ear lobes and multiple contractures (elbows, pelvis, and knees). Figure 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. Figure 1C shows a 6-monthold boy with ...
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... with diastrophic dysplasia have characteristic craniofacial features (Fig. 1). Figure 1A shows a 10-year-old boy with severe short stature, thickened ear lobes and multiple contractures (elbows, pelvis, and knees). Figure 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. ...
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... with diastrophic dysplasia have characteristic craniofacial features (Fig. 1). Figure 1A shows a 10-year-old boy with severe short stature, thickened ear lobes and multiple contractures (elbows, pelvis, and knees). Figure 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. Figure 1C shows a 6-monthold boy with micromelic dwarfism, a characteristic craniofacial contour and contractures of the elbows and knees. ...
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... 1B shows a 2-year-old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. Figure 1C shows a 6-monthold boy with micromelic dwarfism, a characteristic craniofacial contour and contractures of the elbows and knees. Figure 1D shows a 12-year-old girl whose knees had been operated on to relieve the contractures; however, the contractures had recurred. ...
Citations
... In practice, arthrogryposis is a symptom complex rather than a diagnosis; it has various causes and manifests in different recognizable syndromes. Al Kaissi etal diagnosed several children with specific syndromic entities who were previously and wrongly so, given the diagnosis of arthrogryposis multiplex congenital [12][13][14][15][16][17][18] Escobar variant MPS, is predominantly caused by homozygous or compound heterozygous mutation in the CHRNG gene. However, few cases of the lethal form were also caused by mutations in the CHRNG gene [4]. ...
... Arthrogryposis multiplex is a symptom complex rather than a diagnosis; it has various causes, and it is not a single entity but may be due to a variety of genetically determined disorders. [12][13][14][15][16][17][18]38 There were several reports described the various presentations of patients with Escobar syndrome. 4,8,9,[33][34][35][36] The condition has now been mapped, and mutations found in the embryonal gamma subunit of the acetylcholinereceptor (CHRNG) by Morgan et al. 4 [38][39][40][41][42][43][44][45][46] In this study, we screened for mutations in the CHRNG gene in related individuals (4/7). ...
Abstract
Background: Children born with multiple congenital contractures have been almost always given the diagnosis of arthrogryposis multiplex congenita. Arthrogryposis is a descriptive term, not a specific disease entity. A heterogeneous group of conditions associated with multiple congenital joint contractures (mostly syndromic) should be considered.
Methods: The records of seven children (four boys and three girls with aged 6months- 11 years) of different ethnic origins have been included in this study. The constellation of specific craniofacial dysmorphic features, spine malformation complex, and appendicular skeletal abnormalities in addition to camptodactyly, talipes equinovarus and rocker-bottom feet were a cluster of malformation complex encountered in our patients. Via comprehensive clinical and imaging study (3D reconstruction CT scan), definite diagnosis of Escobar syndrome has been approached.
Results: The clinical and imaging phenotype was the key factor towards etiological understanding, treatment and genotype confirmation. We identified compound heterozygous mutations (c.459dupA [p.Val154Serfs*24] and c.794T>G [p.Leu265Serfs*24] of the CHRNG gene in four patients. Bilateral flexion contractures of the knees have been treated by using Iliazarov external fixator. Simultaneous corrections of scoliosis have been achieved by applying either dual traditional growing rods or single growing rods.
Conclusion: The clinical and radiological phenotypic characterizations are the fundamental tool in differentiating Escobar from other forms of multiple contractures. The aim of this study are three folds, firstly to demonstrate the importance of detecting the etiological understanding in children presented with multiple contractures, secondly to refute the general conception among the vast majority of pediatricians and orthopedic surgeons that arthrogryposis multiplex is a diagnostic entity. And thirdly, we were able to detect severe spine deformity via 3D reconstruction CT scan, namely unsegmented posterior spinal bar.
... Diastrophic dysplasia is a rare autosomal recessive skeletal dysplasia that manifests as shortened limbs, spinal abnormalities, joint abnormalities, and "Hitchhiker thumb." 28 Clinically, patients have proximal abducted thumbs and great toe, joint contractures, short limbs, cleft palate, normal intellect, cervical kyphosis, and club feet. Radiographs demonstrate characteristic abducted, hypermobile, proximally placed thumb (hitchhiker's thumb), marked shortening of the first metacarpal with irregular lengthened other metacarpals, ankylosis of proximal interphalangeal joints, and bizarre ossification of the hand bones (►Fig. ...
... 12). 28 Epiphyseal and metaphyseal irregularity in distal femur and tibia with V-shaped or chevron deformities are other features (►Fig. 12). ...
Skeletal dysplasias or osteochondrodysplasias comprise a large heterogeneous group of genetic disorders and possess significant overlap on imaging, which adds to the dilemma of the reporting radiologist. These entities are routinely evaluated with a detailed skeletal survey and hand radiographs form a crucial part of a complete survey. Certain conditions have characteristic imaging findings that enable a diagnosis be made on hand radiograph alone. Additionally, hand radiographs may also demonstrate findings that may be suggestive of a particular diagnosis/differential diagnoses and would warrant further assessment for proving the same. We aim to demonstrate the use of hand radiographs in diagnosis of various such entities through this review. Although they cannot replace a complete skeletal survey in the diagnosis, hand radiographs performed for other indications might alert a radiologist to the diagnosis of an unsuspected skeletal dysplasia.
... The current approach in the general management of patients with SLS26A2-related skeletal dysplasias, including orthopedic surgery for children with major musculoskeletal involvement, remains empirical and does not account genetic variants [28]. The detailed knowledge of clinical and genetic correlations can influence this approach. ...
Multiple epiphyseal dysplasias (MED) are a clinically and genetically heterogeneous group of skeletal dysplasias with a predominant lesion in the epiphyses of tubular bones. Variants in the SLC26A2 gene cause their autosomal recessive form (rMED or MED type 4). The accumulation of data regarding the genotype–phenotype correlation can help in the diagnosis and proper management of these patients. The aim of this study was to survey the clinical and genetic characteristics of 55 patients with MED type 4 caused by variants in the SLC26A2 gene. Diagnosis confirmation was carried out by radiography and custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. This was followed by the validation of the identified variants using automated Sanger sequencing (for six patients) and the direct automatic Sanger sequencing of the coding sequence and the adjacent intron regions of the SLC26A2 gene for 49 patients. Based on the clinical and genetic analysis of our sample of patients, two main MED type 4 phenotypes with early and late clinical manifestations were identified. An early and more severe form of the disease was observed in patients with the c.835C > T variant (p.Arg279Trp), and the late and milder form of the disease was observed in patients with the c.1957T > A variant (p.Cys653Ser) in the homozygous or compound heterozygous state with c.26 + 2T > C. It was also shown that only three pathogenic variants were found in 95.3% of the alleles of Russian patients with MED type 4: c.1957T > A (p.Cys653Ser), c.835C > T (p.Arg279Trp), and c.26 + 2T > C; thus, it can be assumed that the primary analysis of these variants will contribute to the optimal molecular genetic diagnostics of MED type 4.
... There is currently no curative treatment for DTD. The affected individuals are mainly treated with physiotherapy and corrective orthopedic surgery [22][23][24][25]. However, recent animal studies have shown promising results from treatment with N-acetylcysteine (NAC), which acts as an intracellular source of sulfate. ...
Diastrophic dysplasia (DTD) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2 and is particularly common in the Finnish population. However, the disease incidence in Finland and clinical features in affected individuals have not been recently explored. This registry-based study aimed to investigate the current incidence of DTD in Finland, characterize the national cohort of pediatric subjects with DTD and review the disease-related literature. Subjects with SLC26A2-related skeletal dysplasia, born between 2000 and 2020, were identified from the Skeletal dysplasia registry and from hospital patient registry and their clinical and molecular data were reviewed. Fourteen subjects were identified. Twelve of them were phenotypically classified as DTD and two, as recessive multiple epiphyseal dysplasia (rMED). From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. Two subjects with rMED phenotype were compound heterozygous for p.Arg279Trp and p.Thr512Lys variants. The variable phenotypes in our cohort highlight the wide spectrum of clinical features, ranging from a very severe form of DTD to milder forms of DTD and rMED. The incidence of DTD in Finland has significantly decreased over the past decades, most likely due to increased prenatal diagnostics.
... Genotype and phenotype of patient DISCO-JST8 strongly suggest the diagnosis of diastrophic dysplasia (DTD), although we are unable to determine whether the variants occur in trans or in cis because of the unavailability www.moleculartherapy.org of the mother's sample. Typical features of DTD include limb shortening, normal-sized skull, hitchhiker thumbs, and spinal deformities, 13 whereas language retardation and testicle hypoplasia are not associated with DTD. ...
Congenital limb malformations (CLM) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study is to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely-pathogenic single nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p=0.012), or more than one limb affected (p=0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.
... Cavovarus deformity which is often present is treated with the Ponseti method of casting in patients in the age group <6 months. There is a need for soft-tissue release in patients with after the walking age and in resistant cases, it may need aggressive release [6]. Metatarsus adductus deformity if Discussion rudimentary femoral epiphysis with fragmentation (Fig. 3). ...
Introduction:
Diastrophic dysplasia (DTD) results from SCN26A2 gene mutation, with autosomal recessive inheritance and widely variable phenotype. The gene has been mapped to chromosome 5q32-q33.1.
Case report:
We present a case of a 4-year-old female with short stature, bilateral feet and knee deformity, and dysplastic facies. SCN26A2 mutations were seen in patient as well as parents. She underwent multiple orthopedic procedures involving metatarsals, gastrosoleus, and distal femur. Based on typical clinical features, DTD was suspected. Genetic studies of patient and parents provided the exact diagnosis in this case.
Conclusion:
Genetic diagnosis and family counseling are important caveat of management. Key features like ear abnormalities help to suspect diagnosis which requires a high index of suspicion. Associated bony and soft-tissue abnormalities of lower limb may require surgical intervention for improvement of gait, functions, and cosmesis.
Clubfoot is one of the most common orthopedic birth defects. The Ponseti casting method is considered the gold standard for treating clubfoot. The majority of clubfeet occur in isolation and respond well to the traditional Ponseti method. The remaining clubfeet are atypical and usually associated with chromosomal abnormalities, neuromuscular conditions, and/or syndromes. These feet are considered the most difficult to treat and have routinely resulted in extensive surgical interventions as they inconsistently fully correct with the traditional Ponseti method. However, all atypical clubfeet benefit from the modified Ponseti technique. This does not mean that these feet will achieve full correction without some surgical intervention. These feet will gain some benefit from serial casting making any surgery necessary a more thoughtful “a la carte” procedure. Clinical presentation, response to treatment, bracing, and relapse are different in atypical clubfoot, and expectations should be adjusted accordingly. The heterogeneous nature and characteristics of atypical clubfoot are reviewed and detailed in this chapter. The modified treatment protocols and the solutions to the additional challenges encountered in these difficult feet are also discussed.KeywordsCongenital Talipes Equinovarus CTEVAtypical clubfootTibial bowingDrop toe signNon-idiopathic clubfootArthrogryposisMyelomeningoceleNeurogenic clubfootPeroneal nerve palsyTreatment-resistant clubfoot
Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter crucial for sulfate uptake and glycosaminoglycan (GAG) sulfation. Research on a DTD animal model has suggested possible pharmacological treatment approaches. In view of future clinical trials, the identification of non-invasive biomarkers is crucial to assess the efficacy of treatments. Urinary GAG composition has been analyzed in several metabolic disorders including mucopolysaccharidoses. Moreover, the N-terminal fragment of collagen X, known as collagen X marker (CXM), is considered a real-time marker of endochondral ossification and growth velocity and was studied in individuals with achondroplasia and osteogenesis imperfecta. In this work, urinary GAG sulfation and blood CXM levels were investigated as potential biomarkers for individuals affected by DTD. Chondroitin sulfate disaccharide analysis was performed on GAGs isolated from urine by HPLC after GAG digestion with chondroitinase ABC and ACII, while CXM was assessed in dried blood spots. Results from DTD patients were compared with an age-matched control population. Undersulfation of urinary GAGs was observed in DTD patients with some relationship to the clinical severity and underlying SLC26A2 variants. Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. In summary, both non-invasive biomarkers are promising assays targeting various aspects of the disorder including overall metabolism of sulfated GAGs and endochondral ossification.
Diastrophic dysplasia (DTD) is an autosomal, recessively inherited skeletal dysplasia characterized by short limbs, normal-sized skull, cleft palate in one third of patients, characteristic swelling of the pinnae cartilage, contractures of the large joints with deformities, spinal abnormalities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and a distinct brachydactyly associated with the characteristic hitchhiker thumbs. Ultrasound findings include shortened appendicular bones, scoliosis, deviated thumbs and halluxes, and micrognathia. DTD is caused by homozygosity or compound heterozygosity for mutations in the SLC26A2 gene; other allelic and more severe disorders include achondrogenesis type IB and atelosteogenesis type II.
This update summarizes select articles pertaining to limb lengthening and deformity correction that were published between January 1, 2014, and December 31, 2014.
### Guided Growth
Angular deformities in growing children can often be corrected with use of guided growth. Although two-hole 3.5-mm reconstruction plates with 4-mm cancellous screws provide an economical and effective alternative to design-specific, tension-band plating systems, their 10% screw breakage rate merits consideration of the use of larger (4.5-mm) cortical screws1. Caution must be used when applying medial distal-femoral temporary tension-band plates to prevent impingement or injury to the medial patellofemoral ligament2. Despite more implant-related complications, medial malleolar transphyseal screws in comparison with tension-band plates can result in faster corrections3. Ankle valgus in children with spina bifida can be effectively corrected with the use of a medial malleolar screw4. Following guided growth treatment, physical therapy readily resolves the delayed return to function that most commonly occurs in children who are older than eleven years of age and in patients who are undergoing bilateral procedures, distal femoral plating, or procedures involving four or more implants5. A modified technique for insertion of tension-band plates has decreased operative time and incision size6. Parallel compared with divergent screw configuration was favorable in a synthetic-bone guided-growth model7. Tension-band plates at the trochanteric apophysis may have a role as a non-osteotomy containment strategy for Legg-Calve-Perthes disease8.
### Limb-Length Discrepancy
A comparison of lateral elbow and left hand radiographs for assessing skeletal maturity revealed that the elbow radiographs were preferred during the growth spurt and the hand radiographs were more useful following the growth spurt9. When evaluating the effectiveness of percutaneous physeal ablation with a drill and burr technique (the Canale method) compared with that of transphyseal screws (the Metaizeau method), …
